According to WHO estimates, considerably more than 15 million people are currently infected with HIV-1 or HIV-2.
Inhibitors of reverse transcriptase, an enzyme which converts retroviral RNA into DNA, such as 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI), and also trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-.beta.-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide and dideoxycytidine, and also adriamycin, have primarily been used hitherto for treating retroviral diseases such as AIDS. Attempts are also being made to introduce the T4 cell receptor, which is present in the human body on certain cells of the immune system and which is responsible for anchoring infectious viral particles and introducing them into these cells, and is consequently responsible for their ability to infect, into the body, for example as a recombinant molecule or molecular fragment. This would have the effect of titrating out binding sites for the virus so that the virions would no longer be able to bind to the cells. Compounds which use other means to prevent the virus penetrating through the cell membrane, such as polymannoacetate, are also used.
In addition to this, the first clinical experiments in which a hydroxyethylene isostere, N-tert-butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2-quinolylcarbonyl -L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro 31-8959) is used as an inhibitor of the HIV protease have been reported. This compound had an inhibitory effect on HIV protease in vitro and suppressed viral replication in cell experiments, and useful blood levels were achieved in rodents even with oral administration (see Roberts, N. A., et al., Biochemical Soc. Transactions 20, 513-516 (1992)); useful blood levels were also achieved in humans (see, for example, G. J. Muirhead et al., Brit. J. Clin. Pharmacol. 34, 170P-171P (1992)). A so-called "surrogate marker" (titre of the CD4 lymphocytes in the blood, whose decline in untreated patients represents a measure of the development of the AIDS disease) demonstrated the first positive effects in AIDS patients (see "Roche statement on HIV Proteinase Inhibitor (Ro 31-8959) European Trials Results", which was distributed to participants at the 9th International Congress on AIDS in Berlin, Jun. 7-11, 1993).
In the AIDS viruses, HIV-1 and HIV-2, and in other retrovimses, for example the corresponding viruses in cats (FIV) and monkeys (SIV), proteolytic maturation, for example of the core proteins of the virus, is effected by an aspartate protease, such as the HIV protease. No infectious viral particles can be produced without this proteolytic maturation. On the basis of the central role played by the said aspartate proteases, such as HIV-1 protease or HIV-2 protease, in viral maturation, and on the basis of experimental results, for example obtained with infected cell cultures, it is assumed that effective prevention in vivo of the maturation step which is brought about by this protease will prevent mature virions from being assembled. Consequently, appropriate inhibitors can be employed therapeutically.
It is the object of the present invention to prepare a novel class of compounds which also possess, in particular, favourable pharmacological properties, such as good pharmacokinetics, bioavailability and/or good tolerability.